OA11645A

OA11645A - Alkynyl-substituted quinolin-2-one derivatives useful as anticancer agents.

Info

Publication number: OA11645A
Application number: OA1200100051A
Authority: OA
Inventors: Susan Deborah La Greca; Joseph Peter Lyssikatos
Original assignee: Pfizer Prod Inc
Priority date: 1998-08-27
Filing date: 1999-08-06
Publication date: 2004-11-16
Also published as: NO20010964D0; MA26680A1; EP1107963A1; NZ509372A; CO5130017A1; EA200100135A1; WO2000012499A1; CA2578326A1; EE200100118A; TNSN99162A1; AP2001002079A0; US6579887B2; CN1314904A; US6294552B1; BRPI9913138B8; PE20000986A1; DZ2880A1; GT199900140A; CA2341690C; SV1999000141A

Abstract

The present invention relates to compounds of formula 1and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are as defined herein. The above compounds of formula 1 are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering the compounds of formula 1 to a mammal requiring such treatment

Description

- # , -1- SUBSTITUTE SHEET * 0116 4 5

ALKYNYL-SUBSTITUTED QUINOLIN-2-ONE DERIVATIVES USEFUL AS ANTICANCER AGENTSBackground of the Invention

This invention relates to a sériés of alkynyl-substituted quinolin-2-one dérivatives that 5 are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Thisinvention also relates to a method of using such compounds in the treatment ofhyperproliferative diseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

Oncogenes frequently encode protein components of signal transduction pathways 10 which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cellsleads to cellular transformation, characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells.Mutation and/or overexpression of certain oncogenes is frequently associated with humancancer. 15 To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnésylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of theenzyme that catalyzes this modification, farnesyl protein transferase, hâve therefore beensuggested as agents to combat tumors in which Ras contributes to transformation. Mutated,oncogenic forms of Ras are frequently found in many human cancérs, most notably in more ΟΛ than 50% of colon and pancreatic carcinomas (Kohl et ah, Science, Vol. 260. 1834 to 1837,1993). The compounds of the présent invention exhibit activity as inhibitors of the enzymefarnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents. Further, the compounds of the présent invention may be active sgainst anytumors that proliferate by virtue of farnesyl protein transferase. 25 WO 97/16443 and WO 97/21701 both relate to farnesyl transferase inhibiting 2- quinolone dérivatives.

Summary of the InventionThe présent invention relates to compounds of formula 1

and to pharmaceutically acceptable salts, prodrugs and solvatés thereof wherein: -2- 011645 the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2-onering is a single or double bond; R’ is selected from H, C,-C10 alkyl, -(CR13R14)qC(O)R12, -(CR13R14)<,C(O)OR1S,-(CR13R’4)qOR12, -{CR13R14)qSO2R’5, -(CR13R14)t(C3-C10 cycloalkyl), -(CR13R14),(C6-C10 aryl), 5 and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is aninteger from 1 to 5, said cycloalkyl, aryl and heterocyclic R’ groups are optionally fused to aC6-C10aryl group, a Cs-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; andthe foregoing R1 groups, except H but including any optional fused rings referred to above, areoptionally substituted by 1 to 4 R6 groups; W R2 is halo, cyano, -C(O)OR15, or a group selected from the substituents provided in the définition of R12; each R3, R4, R5, R6, and R7 is independently selected from H, Ci-C10 alkyl, C2-C10alkenyl, halo, cyano, nitro, mercapto, trifluoromethyl, trifluoromethoxy, azido, -OR12, -C(O)R12,-C(O)0R12, -NR13C(O)OR15, -OC(O)R12, -NR13SO2R1s, -SO2NR12R13, -NR13C(O)R12, t5 -C(O)NR12R13, -NR12R13, -CH=NOR12, -S(O)jR12 wherein j is an integer from 0 to 2,-(CR13R14),(C6-C10 aryl), -(CR13R,4),(4-10 membered heterocyclic), -(CR13R14),(C3-C,0cycloalkyl), and -(CR13R14)tCsCR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groupst is an integer from 0 to 5; the cycloalkyl, aryl and heterocyclic moieties of the foregoing groupsare optionally fused to a C6-C10 aryl group, a Cs-C8 saturated cyclic group, or a 4-10membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groupsare optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, -NR13SO2R15, -SO2NR12R13, -C(O)R12, -C(O)OR12,-OC{O)R12, -NR13C(O)OR1S, -NR13C(O)R12. -C(O)NR12R13, -NR12R13, -OR12, CrC,0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, -(CR13R14)i(C6-C10 aryl), and -(CR13R14)i(4-10 membered 25 heterocyclic), wherein t is an integer from 0 to 5; R8 is H, -OR12. -NR12R13, -NR12C(O)R13, cyano, -C(O)OR13, -SR12, -(CR13R14),(4-10membered heterocyclic), wherein t is an integer from 0 to 5, or CrC6 alkyl, wherein saidheterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents; R9 is -(CR13R14)t(imidazoIyl) wherein t is an integer from 0 to 5 and said imidazolyl3® moiety is optionally substituted by 1 or 2 R6 substituents; each R10 and R11 is independently selected from the substituents provided in thedéfinition of R6; each R12 is independently selected from H, C,-Ck> alkyl, -(CR13R14),(C3-C,0 cycloalkyl),-(CR13R14),(C6-Cio aryl), and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer 35 from 0 to 5; said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-Ci0aryl group, a CS-CB saturated cyclic group, or a 4-10 membered heterocyclic group; and theforegoing R12 substituents, except H, are optionally substituted by 1 to 3 substituents -3- n -} 4 x / r υ I f ο b independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido.-C(O)R13, -C(O)OR13, -OC(O)R13, -NR13C(O)R14, -C(0)NR13R14, -NR’3R'4, hydroxy, C,-C6alkyl, and CrC6 alkoxy; each R13 and R14 is independently H or CvC6 alkyl, and where R13 and R’4 are as-(CR13R14)<, or (CR13R14)t each is independently defined for each itération of q or t in excess of1; R1S is selected from the substituents provided in the définition of R12 except R15 is notH: R16 is selected from the list of substituents provided in the définition of R12 and-SiR17R18R19; R17, R18 and R19 are each independently selected from the substituents provided inthe définition of R12 except R17, R18 and R19 are not H; and provided that at least one of R3, R4 and R5 is -(CR13R14)tC2CR16 wherein t is aninteger from 0 to 5 and R13, R14, and R16 are as defined above.

Preferred compounds of formula 1 include those wherein R1 is H, CrCe alkyl, orcyclopropylmethyl; R2 is H; R3 is -CsCR16; and R8 is -NR12R13, -OR12, or a heterocyclic groupselected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group isoptionally substituted by an R6 group. More preferred compounds include those wherein R9 isimidazolyl optionally substituted by CrC6 alkyl; R8 is hydroxy, amino, or triazolyl; and R4, R5, R10and R11 are each independently selected from H and halo.

Other preferred compounds formula 1 include those wherein R1 is -(CR,3R14)t(C3-Ciocycloalkyl) wherein t is an integer from 0 to 3; R2 is H; R3 is -CsCR16; and R8 is -NR12R13, -OR12, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl,wherein said heterocyclic group is optionally substituted by an R8 group. More preferredcompounds include those wherein R9 is imidazolyl optionally substituted by CrC6 alkyl; R8 ishydroxy, amino, or triazolyl; R4, R5, R10 and R11 are each independently selected from H andhalo; and R1 is cyclopropylmethyl.

Other preferred compounds formula 1 include those wherein R3 is ethynyl and the othersubstituents are as defined above.

Spécifie preferred compounds include the following: 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer A); 6-((4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer B); 6-[Amino-(4-chloro-phenyI)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyt)-1-methyl-1H-quinolin-2-one (enantiomer A); -4- *··.<*·/** ! ü*tû 6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imida2ol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer B); 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imida2ol-4-yl)-methyl]-4-(3-ethynyl-4- fluoro-phenyl)-1-methyl-1H-quinolin-2-one; 5 and the pharmaceutically acceptable salts, prodrugs and solvatés of the foregoing compounds, as well as stereoisomers of the foregoing compounds.

The présent invention also relates to intermediates of formula 28

wherein R1, R2, R3, R4, Rs, R6, R7, R10 and R11 are as defined above.

The présent invention also relates to the following spécifie intermediates which may 10 ,;be used in the préparation of the compounds of the présent invention 6-[(4-Chloro-phenyi)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methy!-4-{3- trimethyisilanylethynyl-phenyl)-1H-quinolin-2-one 6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1- methyl-4-(3-trimethylsilanylethyny!-phenyl)-1 H-quinolin-2-one15 6-(4-Chloro-benzoyl)-1 -methyl-4-(3-trimethylsilanylethynyl-phenyl)-1 H-quinolin-2-one 6-(4-Chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinplin-2-one 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H- quinolin-2-one.

The présent invention also relates to a method of preparing a compound of formula 120 wherein R3 is ethynyl, which comprises treating a compound of formula 29 -5- 011645

wherein R1, R2, R4, R5, R6, R7, R8, R9, R10 and R” are as defined above withtetrabutylammonium fluoride.

This invention also relates to a method for the treatment of abnormal cell growth in amammal, including a human, comprising administering to said mammal an amount of a 5 compound of the formula 1, as defined above, or a pharmaceutically acceptable sait, prodrug orsolvaté thereof, that is effective in inhibiting farnesyi protein transferase. In one embodiment ofthis method, the abnormal cell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocularmelanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach 10 cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinomaof the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva,Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of theendocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of theadrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate 15 cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, neoplasms of the centralnervous System (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitaryadenoma, or a combination of one or more of the foregoing cancers. In another embodiment ofsaid method, said abnormal cell growth is a benign proliférative disease, including, but not limited 20 to, psoriasis, benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of acompound of the formula 1, as defined above, or a pharmaceutically acceptable sait, prodrug orsolvaté thereof, that is effective in treating abnormai cell growth. 25 This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal a therapeutically effective amount of acompound of formula 1, or a pharmaceutically acceptable sait, prodrug or solvaté thereof, incombination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, -6- 011645 alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, andanti-androgens.

The présent invention also relates to a method for the treatment of an infection in a5 mammal, including a human, that is facilitated by famesyl protein transferase, such as hepatitusdelta virus or malaria, which comprises administering to said mammal a therapeutically effectiveamount of a compound of formula 1 or a pharmaceutically acceptable sait, prodrug or solvaté thereof.

This invention also relates to a pharmaceutical composition for the treatment of10 abnormal cell growth in a mammal, including a human, comprising an amount of a compound ofthe formula 1, as defined above, or a pharmaceutically acceptable sait, prodrug or solvatéthereof, that is effective in inhibiting famesyl protein transferase, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormal cell growth is cancer,including, but not limited to, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of 15 the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal région, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, , cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer 20 of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma,carcinoma of the rénal pelvis, neoplasms of the central nervous System (CNS), primary CNSlymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or 25 more of the foregoing cancers. In another embodiment of said pharmaceutical composition, saidabnormal cell growth is a benign proliférative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a pharmaceutical composition for the treatment ofabnormal cell growth in a mammal, including a human, comprising an amount of a compound of 30 the formula 1, as defined above, or a pharmaceutically acceptable sait, prodrug or solvatéthereof, that is effective in treating abnormal cell growth, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for the treatment ofabnormal cell growth in a mammal, including a human, which comprises a therapeutically 35 effective amount of a compound of formula 1, as defined above, or a pharmaceuticallyacceptable sait, prodrug or solvaté thereof, in combination with a pharmaceutically acceptablecarrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating -7- 011645 agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors,enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.

This invention also relates to a pharmaceutical composition for the treatment of aninfection in a mammal, including a human, that is facilitated by farnesyl protein transferase, suchas malaria or hepatitus delta virus, comprising an amount of a compound of the formula 1, asdeftned above, or a pharmaceuticalfy acceptable sait, prodrug or solvaté thereof, that is effectivein treating abnormal cell growth, and a pharmaceutically acceptable carrier. "Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growththat is independent of normal regulatory mechanisms (e.g., ioss of contact inhibition). Thisincludes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Rasoncogene; (2) tumor cells in which the Ras protein is activated as a resuit of oncogenic mutationin another gene; (3) benign and malignant cells of other proliférative diseases in which aberrantRas activation occurs; and (4) any tumors that proliferate by virtue of farnesyl protein transferase.

The term "treating", as used herein, unless otherwise indicated, means reversing,alleviating, inhibiting the progress of, or preventing the disorder or condition to which such termapplîes, or one or more symptoms of such disorder or condition. The term "treatment", as usedherein, unless otherwise indicated, refers to the act of treating as "treating” is defmedimmediately above.

The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro.bromo or iodo. Preferred halo groups are fluoro, chloro and bromo:

The term "alkyl", as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight or branched moieties.

The term "cycloalkyP, as used herein, unless otherwise indicated, includes cyclic alkylmoieties wherein alkyl is as defmed above.

The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon double bond wherein alkyl is as defined above.

The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moietieshaving at least one carbon-carbon triple bond wherein alkyl is as defmed above.

The term "alkoxy", as used herein, unless otherwise indicated, includes O-alkyl groupswherein alkyl is as defmed above.

The term "aryl", as used herein, unless otherwise indicated, includes an organic radicalderived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.

The term "4-10 membered heterocyclic", as used herein, unless otherwise indicated,includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms,generally 1 to 4 heteroatoms, each selected from O, S and N, wherein each heterocyclic grouphas from 4-10 atoms in its ring System. Non-aromatic heterocyclic groups include groups havingonly 4 atoms in their ring System, but aromatic heterocyclic groups must hâve at least 5 atoms in -8- 011645 their ring System. The heterocyclic groups include benzo-fused ring Systems and ring Systemssubstituted with one or more oxo moieties. An example of a 4 membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5 membered heterocyclic group is thiazolyland an example of a 10 membered heterocyclic group is quinolinyl. Examples of non- 5 aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, tetrahydrothiopyranyl. piperidino, morpholino, thiomorpholino, thioxanyl;piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl. indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, 10 dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicycIo[4.1.0]heptanyl. 3H-indolyi and quinolizinyl. Examples ofaromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyi, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, 15 phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from thecompounds listed above, may be C-attached or N-attached where such is possible. Forinstance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). 20 Where R13 and R14 are as (CR13R14)q or (CR13R14), each is independently defined for each itération of q or t in excess of 1. This means, for instance, that where q or t is 2 alkylenemoieties of the type -CH2CH(CH3)-, and other asymmetrically branched groups, are included.

The term "pharmaceutically acceptable salt(s)", as used herein, unless otherwiseindicated, includes salts of acidic or basic groups that may be présent in the compounds of 25 formula 1. For example, pharmaceutically acceptable salts include sodium, calcium andpotassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Otherpharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate,phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate,lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The 30 préparation of such salts is described below.

The subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in formula 1, butfor the fact that one or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found in nature. Examples of 35 isotopes that can be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C,14C, 1SN, 18O, ’7O, “S. 1SF, and “Cl, respectively. Compounds of the présent invention, -9- 011645 prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of saidprodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms arewithin the scope of this invention. Certain isotopically-labelled compounds of the présentinvention, for exampie those into which radioactive isotopes such as 3H and 14C areincorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H,and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of préparation and'detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can affordcertain therapeutic advantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of formula 1 of this invention andprodrugs thereof can generally be prepared by carrying out the procedures disclosed in theSchemes and/or in the Examples and Préparations below, by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

This invention also encompasses pharmaceutical compositions containing and methodsof treating bacterial infections through administering prodrugs of compounds of the formula 1.Compounds of formula i having free amino, amido, hydroxy or carboxylic groups can beconverted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group ofcompounds of formula 1. The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocystéine, homoserine, ornithine and méthioninesulfone.

Additional types of prodrugs are also encompassed. For instance, free carboxyl groupscan be derivatized as amides or alkyl esters. The amide and ester moieties may incorporategroups including but not limited to ether, amine and carboxylic acid functionalities. Free hydroxygroups may be derivatized using groups including but not limited to hemisuccinates, phosphateesters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in D.Fleisher, R. Bong, B.H. Stewart, Advanced Drug Delivery Reviews (1996) 19. 115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs and sulfateesters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethytethers wherein the acyl group may be an alkyl ester, optionally substituted with groups includingbut not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is anamino acid ester as described above, are also encompassed. Prodrugs of this type aredescribed in R.P. Robinson et al., J. Médicinal Chemistry (1996) 39,10. -10- 011645

Certain compounds of formula 1 may hâve asymmetric centers and therefore exist indifferent enantiomeric forms. Ail optical isomers and stereoisomers of the compounds offormula 1, and mixtures thereof, are considered to be within the scope of the invention. Withrespect to the compounds of formula 1, the invention incîudes the use of a racemate, one ormore enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. In particular,the carbon to which the R8 and R9 groups are attached représente a potential chiral center; theprésent invention encompasses ail stereoisomers based on this chiral center. The compoundsof formula 1 may also exist as tautomers. This invention relates to the use of ail such tautomersand mixtures thereof. Certain compounds of formula 1 may also include oxime moieties, suchas where R3, R4, R5, R6 or R7 is -CH=NOR12, that exist in E or Z configurations. The présentinvention incîudes racemic mixtures of compounds of formula 1 that include such oximemoieties or spécifie E or 2 isomers of such compounds.

Detailed Description of the InventionThe compounds of formula 1 may be prepared as described below.

With reference to Scheme 1 below, the compounds of formula 1 may be prepared by hydrolysing an intermediate ether of formula 2, wherein R is CrC6 alkyl, according to methodsfamiliar to those skilled in the art, such as by stirring the intermediate of formula 2 in anaqueous acid solution. An appropriate acid is, for example, hydrochloric acid. The resultingquinoiinone of formula 1 wherein R1 is hydrogen may be transformed into a quinolinonewherein R1 has a meaning as defined above apart from hydrogen by ΛΖ-alkylation methodsfamiliar to those skilled in the art

Scheme 1

With reference to Scheme 2 below, the compounds of formula 1(b), which arecompounds of formula 1 wherein R8 is hydroxy, may be prepared by reacting an intermediateketone of formula 3 with an intermediate of the formula H-R9, wherein R9 is as defmed aboveand wherein in the imidazolyl moiety of said R9 group a free nitrogen atom may be protectedwith an optional protective group, such as a sulfonyl group (for example, a dimethylaminpsulfonyl group) which can be removed after the addition reaction. Said reaction requires the -11- 011645 presence of a suitable strong base, such as sec-butyl lithium, ίη an appropriate solvent, suchas tetrahydrofuran, and the presence of an appropriate silane dérivative, such as chloro-fert-butyldimethylsilane. The silyl group can be removed with a fluoride source such as tetrabutylammonium fluoride. Other procedures with protective groups analogous to silane dérivativescan also be applied.

Scheme 2

With reference to Scheme 3 below, compounds of formula 1(b-1), which arecompounds of formula 1 wherein the dotted line is a bond and R’ is hydrogen, can beprepared by reacting an intermediate of formula 21 with an intermediate of formula H-R9,wherein R9 is as. described above. The resulting intermediate of formula 22 undergoes ringopening of the isoxazole moiety by stirring it with an acid, such as TiCI3l in the presence ofwater. Subséquent treatment of the resulting intermediate of formula 23 with a suitablereagent, such as R2CH2COCI or R2CH2COOC2H5, wherein R2 is as defined above, yieldseither directly a compound of formula 1 (b-1) or an intermediate which can be converted to acompound of formula 1 (b-1 ) by treatment with a base, such as potassium fezf-butoxide. 10 -12-

01164 B

Scheme 3

1 (b-1)

Intermediates of formula 21 can be prepared by treating an intermediate of formula16, referred to below with respect to Scheme 9, under acidic conditions.

With reference to Scheme 4 below, compounds of formula 1 wherein R8 is a radical offormula -NR,2R13 wherein R12 and R13 are as described above (said compounds are 5 represented below by formula 1(g)), may be prepared by reacting an intermediate of formula13, wherein W is an appropriate leaving group, such as halo, with a reagent of formula 14.Said reaction may be performed by stirring the reactants in an appropriate solvent, such astetrahydrofuran. -13- 10

Compounds of formula 1(g), or other embodiments of formula 1, wherein the dottedline represents a bond can be converted into compounds wherein the dotted line does notrepresent a bond by hydrogénation methods familiar to those skilled in the art. Compoundswherein the dotted line does not represent a bond may be converted into compounds whereinthe dotted iine represents a bond by oxidation methods familiar to those skilled in the art.

With reference to Scheme 5 below, compounds of formula 1 wherein R8 is hydroxy(said compounds being represented by formula 1(b)) may be converted into compounds offormula 1(c), wherein R12 has the meaning described above except it is not hydrogen, bymethods known to those skilled in the art, including O-alkylation or O-acylation reactions; suchas by reacting the compound of formula 1(b) with an alkylating reagent such as R12-W,wherein R12 is as described above, in appropriate conditions, such as in a dipolar aproticsolvent, such as DMF, in the presence of a base, such as sodium hydride. W is a suitableieaving group, such as a halo group or a sulfonyl group.

Scheme 5

15

As an alternative to the above reaction procedure, compounds of formula 1 (c) mayalso be prepared by reacting a compound of formula 1(b) with a reagent of formula R12-OH,wherein R12 is as described above, in acidic medium.

Compounds of formula 1(b) may also be converted into compounds of formula 1 (g),wherein R12 is hydrogen and R13 is replaced with Ci-Ce alkylcarbonyi, by reacting compoundsof formula 1(b) in acidic medium, such as sulfuric acid, with C,-C6 alkyl-CN in a Ritter-type -14- 011645 10 reaction. Further, compounds of formula 1(b) may also be converted into compounds offormula 1 (g), wherein R12 and R13 are hydrogen, by reacting a compound of formula 1(b) withammonium acetate and subséquent treatment with NH3(aq.).

With reference to Scheme 6 below, compounds of formula 1(b), referred to above,may also be converted into compounds of formula 1 (d), wherein R8 is hydrogen. by submittinga compound of formula 1(b) to appropriate reducing conditions, such as stirring intrifluoroacetic acid in the presence of an appropriate reducing agent, such as sodiumborohydride, or, alternatively, stirring the compound of formula 1(b) in acetic acid in thepresence of formamide. Further, the compound of formula 1(d) wherein R8 is hydrogen maybe converted into a compound of formula 1(e) wherein R12 is C,-C,o alkyl by reacting thecompound of formula 1{d) with a reagent of formula 5, wherein W is an appropriate leavinggroup, in an appropriate solvent, such as diglyme, in the presence of a base, such aspotassium ierf-butoxide.

Scheme 6

R1—W

With reference to Scheme 7 below, compounds of formula 1 may be prepared byreacting a nitrone of formula 6 with the anhydride of a carboxyiic acid, such as aceticanhydride, thus forming the corresponding ester on the 2-position of the quinoiine moiety.Said quinoiine ester can be hydrolyzed in situ to the corresponding quinolinone using a base,such as potassium carbonate. 15 -15-

Alternatively, compounds of formula 1 can be prepared by reacting a nitrone offormula 6 with a sulfonyl containing electrophilic reagent, such as p-toluenesulfonylchloride, inthe presence of a base, such as aqueous potassium carbonate. The reaction initially involvesthe formation of a 2-hydroxy-quinoline dérivative which is subsequently tautomerized to thedesired quinolinone dérivative. The application of conditions of phase transfer catalysis, whichare familiar to those skilled in the art, may enhance the rate of the reaction.

Compounds of formula 1 may also be prepared by an intramolecular photochemicalrearrangement of compounds of formula 6, referred to above. Said rearrangement can becarried out by dissolving the reagents in a reaction-inert solvent and irradiating at awavelength of 366 nm. It is advantageous to use degassed solutions and to conduct thereaction under an inert atmosphère, such as oxygen-free argon or nitrogen gas, in order tominimize undesired side reactions or réduction of quantum yield.

The substituents of the compounds of formula 1 may be converted to othersubstituents falling within the scope of formula 1 via reactions or functional grouptransformations familiar to those skilled in the art. A number of such transformations arealready described above. Other examples are hydrolysis of carboxylic esters to thecorresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylicacids or amines; hydrolysis of nitriles to the corresponding amides; amino groups on imidazoleor phenyl moieties may be replaced by hydrogen by diazotation reactions familiar to thoseskilled in the art, and subséquent replacement of the diazo-group by hydrogen; alcohols maybe converted into esters and ethers; primary amines may be converted into secondary ortertiary amines; double bonds may be hydrogenated to the corresponding single bond.

With reference to Scheme 8 below, intermediates of formula 3, referred to above, maybe prepared by reacting a quinolinone dérivative of formula 8 with an intermediate of formula9, or a functional dérivative thereof, under appropriate conditions, such as in the presence of astrong acid (for example, polyphosphoric acid) in an appropriate solvent. The intermediate offormula 8 may be formed by cyclization of an intermediate of formula 7 by stirring in thepresence of a strong acid, such as polyphosphoric acid. Optionally, said cyclization reaction -16- 011645 may be followed by an oxidation step, which can be performed by stirring the intermediateformed after cyclization in an appropriaîe solvent, such as a halogenated aromatic solvent (forexample, bromobenzene), in the presence of an oxidizing agent, such as bromine or iodine.At this stage, the R1 substituent may be changed to a different moiety by a functional grouptransformation reaction familiar to those skilled in the art.

Scheme 8

10

With reference to Scheme 9 below, intermediates of formula 3{a-1), which areintermediates of formula 3 wherein the dotted line is a bond and R1 and R2 are hydrogen, canbe prepared starting from an intermediate of formula 17, which is conveniently prepared byprotecting the corresponding ketone. Said intermediate of formula 17 is stirred with anintermediate of formula 18 in the presence of a base, such as sodium hydroxide, in anappropriate solvent, such as an alcoho! (for example, methanol). The resulting intermediate offormula 16 will undergo hydrolysis of the ketal and ring opening of the isoxazole moiety bystirring the intermediate of formula 16 with an acid, such as TiCI3l in the presence of water.Subsequently, acetic anhydride can be used to préparé an intermediate of formula 15, whichwill undergo ring closure in the presence of a base, such as potassium ferf-butoxide.

Intermediates of formula 3(a-1) can be converted to intermediates of formula 3(a), i f which are intermediates of formula 3 wherein the dotted line represents a bond, R2 ishydrogen, and R1 is other than hydrogen as defined above, using /V-alkylation proceduresfamiliar to those skilled in the art. 15 -17- 011645

Scheme 9

With reference to Scheme 10 below, an alternative method of preparing intermediatesof formula 3(a-1), wherein R1 is hydrogen, begins with an intermediate of formula 16 whichcan be converted to an intermediate of formula 19 using catalytic hydrogénation conditions,such as by using hydrogen gas and palladium on carbon in a reaction-inert, solvent such astetrahydrofuran (THF). The intermediates of formula 19 can be converted into an intermediateof formula 20 by submitting the intermediate of formula 19 to an acétylation reaction, such asby treatment with the anhydride of a carboxylic acid (for example, acetic anhydride) in areaction-inert solvent, such as toluene, and subséquent treatment with a base, such aspotassium ferf-butoxide, in a reaction-inert solvent, such as 1,2-dimethoxyethane. The -18- 011645 intermediate of formula 3(a-1 ) can be obtained by subjecting the intermediate of formula 20 to acidic conditions.

Scheme 10 10

With reference to Scheme 11 below, the intermediate of formula 2, referred to above,may be prepared by reacting an intermediate of formula 10, wherein W is an appropriateleaving group, such as halo, with an intermediate ketone of formula 11. This reaction is doneby converting the intermediate of formula 10 into a organometallic compound, by stirring it witha strong base such as butyl lithium, and subsequently adding the intermediate ketone offormula 11. Although this reaction gives at first instance a hydroxy dérivative (R8 is hydroxy),said hydroxy dérivative can be converted into other intermediates wherein R8 has anotherdéfinition by performing functional group transformations familiar to those skilled in the art.

With reference to Scheme 12 below, the intermediate nitrones of formula 6 can beprepared by /V-oxidizing a quinoline dérivative of formula 12 with an appropriate oxidizingagent, such as m-chloro-peroxybenzoic acid or H2O2, in an appropriate solvent, such asdichloromethane. -19- 011645

Scheme 12

10 15

Said /V-oxidation may also be carried out on a precursor of a quinoline of forumula 12.

The intermediate of formula 12 may be metabolized in vivo into compounds of formula1 via intermediates of formula 6. Hence, intermediates of formula 12 and 6 may act asprodrugs of compounds of formula 1. Such prodrugs are within the scope of the présentinvention.

With reference to Scheme 13 below, the compound of formula 24, wherein Y isbromo, iodo or trifluoromethanesulfonyloxy, can be reacted to add an R3, R4 or R5 group(addition of R3 is illustrated) of the formula -CsCR16, in particular a terminal alkyne such as(trimethylsilyl)acetylene, using palladium catalysis (with a palladium reagent, such asbis(triphenylphosphine)-palladium(ll) chloride) in the presence of copper (I) salts, such ascopper (I) iodide, in an amine solvent, such as diethylamine, at a température ranging from0°C to 100°C to give a compound of formula 28 wherein R3 is an alkyne as described above.Co-solvents, such as (Λ/,/V-dimethyIformamide) DMF, may be added to help solubilize thereactants. Additional methods of effecting such an alkyne addition are referred to in UnitedStates patent 5,747,498.

Scheme 13

With reference to Scheme 14 below, the compound of formula 26 can be prepared byreacting a compound of formula 25 with an intermediate of formula 27 where R12 is H orphenyl. This reaction requires the presence of a suitable base, such as ferf-butyl lithium -20- 011645 (when R12 = H) or lithium 2,2,6,6,-tetramethylpiperidine (when R12 = phenyl), in an appropriatesolvent, such as THF. The -SR12 group can be reductively removed from the compound offormula 26 with RANEY™ nickel or oxidatively with nitric acid or aqueous hydrogen peroxide inacetic acid.

10 15

The compounds of formula 1 and some of the intermediates described above may hâve one or more stereogenic centers in their structure. Such stereogenic centers may bé présent in a R or a S configuration. Oxime moieties. such as where R3, R4, R5, R6 or R7 * * ra * * * * al is -CH=NOR12, may exist in E or Z configurations.

The compounds of formula 1' as prepared in the above processes are generally racemic mixtures of enantiomers which can be separated from one another following resolution procedures familiar to those skilled in the art. The racemic compounds of formula 1 may be converted into the corresponding diastereomeric sait forms by reaction with a suitable chiral acid. Said diastereomeric sait forms are subsequently separated, for example, by sélective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula 1involves liquid chromatography using a chiral stationary phase. Said pure stereochemicallyisomeric forms may also be derived from the corresponding pure stereochemically isomericforms of the appropriate starting materials, provided that the reaction occurs sterospecifically.Preferably if a spécifie stereoisomer is desired, said compound will be synthesized bystereospecfic methods of préparation. These methods will advantageously employenantiomerically pure starting materials. 20 -21- 011645

The compounds of formula 1 that are basic in nature are capable of forming a widevariety of different salts with various inorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animais, it is often désirable in practice toinitially isolate the compound of formula 1 from the reaction mixture as a pharmaceuticallyunacceptable sait and then simply convert the latter back to the free base compound bytreatment with an alkaline reagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition sait. The acid addition salts of the base compounds ofthis invention are readily prepared by treating the base compound with a substantially équivalentamount of the chosen minerai or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or éthanol. Upon évaporation of the solvent, the desired solidsait is readily obtained. The desired acid addition sait can also be precipitated from a solution ofthe free base in an organic solvent by adding to the solution an appropriate minerai or organicacid. Cationic salts of the compounds of formula 1 are similariy prepared except throughreaction of a carboxy group with an appropriate cationic sait reagent, such as sodium,potassium, calcium, magnésium, ammonium, Ν,Ν'-dibenzylethylenediamine, N-methylglucamine(meglumine), ethanolamine, tromethamine, or diethanolamine.

The compounds of formula 1 and their pharmaceutically acceptable salts and solvatés(hereinafter referred to, collectively, as "the therapeutic compounds”) can be administered orally,transdermally (e.g., through the use of a patch), parenterally or topically. Oral administration ispreferred. In general, compounds of the formula 1 and their pharmaceutically acceptable saltsand solvatés are most desirably administered in dosages ranging from about 1.0 mg up to about500 mg per day, preferably from about 1 to about 100 mg per day in single or divided (i.e.,multiple) doses. The therapeutic compounds will ordinarily be administered in daily dosagesranging from about 0.01 to about 10 mg per kg body weight per day, in single or divided doses.Variations may occur depending on the weight and condition of the person being treated and theparticular route of administration chosen. In some instances, dosage levels below the lower limitof the aforesaid range may be more than adéquate, while in other cases still larger doses may beemployed without causing any harmfu! side effect, provided that such larger doses are firstdivided into several small doses for administration throughout the day.

The therapeutic compounds may be administered alone or in combination withpharmaceutically acceptable carriers or diluents by either of the two routes previousiy indicated,and such administration may be cam'ed out in single or multiple doses. More particularly, thenovel therapeutic compounds of this invention can be administered in a wide variety of differentdosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriersin the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams,salves, suppositories, jellies, gels, pastes, lotions, ointments, élixirs, syrups, and the like. Suchcarriers include solid diluents or fillers, stérile aqueous media and various non-toxic organic -22-

Wf 011645 solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored.

For oral administration, tablets containing various excipients such as microcrystallinecellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed 5 along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like-polyvinyipyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnésium stéarate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred 10 materials in this connection also include lactose or milk sugar as well as high molecular weightpolyethyiene glycols. When aqueous suspensions and/or élixirs are desired for oraladministration, the active ingrédient may be combined with various sweetening or flavoringagents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, éthanol, propylene glycol, glycerin and.various like 15 combinations thereof.

For parentéral administration, solutions of a therapeutic compound in either sesame orpeanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should besuitably buffered if necessary and the liquid diluent first rendered isotonie. These aqueoussolutions are suitable for intravenous injection purposes. The oily solutions are suitable for 20 intra-articular, intra-muscular and subeutaneous injection purposes. The préparation of ail thesesolutions under stérile conditions is readily accomplished by standard pharmaceutical techniqueswell-known to those skilled in the art

Additionally, it is also possible to administer the therapeutic compounds topically and thismay preferably be done by way of creams, jellies, gels, pastes, oinîments and the like, in 25 accordance with standard pharmaceutical practice.

The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will dépend on the animal species and thedisease or disorder being treated. The therapeutic compounds may be administered to animaisin the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be 30 administered to animais by injection or as an implant. Such formulations are prepared in aconventional manner in accordance with standard veterinary practice. As an alternative thetherapeutic compounds may be administered with the animal feedstuff and for this purpose aconcentrated feed additive or premix may be prepared for mixing with the normal animal feed.

The compounds of formula 1 exhibit activity as Ras farnésylation inhibitors and are 35 useful in the treatment of cancer and the inhibition of abnormal cell growth in mammals,including humans. The activity of the compounds of formula 1 as Ras farnésylation inhibitors -23- 011645 may be determined by their ability, relative to a control, to inhibit Ras farnesyl transferase in vitro.This procedure is described below. A crude préparation of human farnesyl transferase (FTase) comprising the cytosolicfraction of homogenized brain tissue is used for screening compounds in a 96-well assay format.

5 The cytosolic fraction is prepared by homogenizing approx. 40 grams fresh tissue in 100 ml ofsucrose/MgCI2/EDTA buffer (using a Dounce homogenizer; 10-15 strokes), centrifuging thehomogenates at 1000 grams for 10 minutes at 4G, re-centrifuging the supernatant at 17,000grams for 15 minutes at 4G, and then collecting the resulting supernatant. This supernatant isdiluted to contain a final concentration of 50 mM Tris HCl (pH 7.5), 5 mN DTT, 0.2 M KCI, 20 mM W ZnCI2, 1 mM PMSF and re-centrifuged at 178,000 grams for 90 minutes at 4G. The supernatant,termed "crude FTase" was assayed for protein concentration, aliquoted, and stored at -70eC.

The assay used to measure in vitro inhibition of human FTase is a modification of themethod described by Amersham LifeScience for using their Farnesyl transferase (3H)Scintillation Proximity Assay (SPA) kit (TRKQ 7010). FTase enzyme activity is determined in a 15 volume of 100 ml containing 50 mM N-(2-hydroxy ethyl) piperazine-N-(2-ethane sulfonic acid)(HEPES), pH 7.5, 30 mM MgCI2, 20 uM KCI, 5 mM Na2HPO«, 5 mM dithiothreitol (DTT), 0.01%Triton X-100, 5% dimethyl sulfoxide (DMSO), 20 mg of crude FTase, 0.12 mM [3H]-farnesylpyrophosphate ([3H]-FPP; 36000 dpm/pmole, Amersham LifeScience), and 0.2 mM ofbiotinylated Ras peptide KTKCVIS (Bt-KTKCVIS) that is N-terminally biotinylated at its alpha 20 amino group and was synthesized and purified by HPLC in house. The reaction is initiated byaddition of the enzyme and terminated by addition of EDTA (supplied as the STOP reagent in kitTRKQ 7010) following a 45 minute incubation at 37°C. Prenylated and unprenylated Bt-KTKCVIS is captured by adding 10 ml of steptavidin-coated SPA beads (TRKQ 7010) per welland incubating the reaction mixture for 30 minutes at room température. Thé amount of 25 radioactivity bound to the SPA beads is determined using a MicroBeta 1450 plate counter.Under these assay conditions, the enzyme activity is linear with respect to the concentrations ofthe prenyl group acceptor, Bt-KTKCVIS, and crude FTase, but saturating with respect to theprenyl donor, FPP. The assay reaction time is also in the linear range.

The test compounds are routinely dissolved in 100% dimethyl sulfoxide (DMSO). 30 Inhibition of farnesyl transferase activity is determined by calculating percent incorporation oftritiated-farnesyl in the presence of the test compound vs. its incorporation in control wells(absence of inhibitor). IC50 values, that is, the concentration required to produce half maximalfarnésylation of Bt-KTKCVIS, is determined from the dose-responses obtained.

The following Examples further illustrate the invention. In the following Examples, “Et” 35 refers to ethyl, “Me" refers to methyl, and “Ac” refers to acetyl. -24- > J > 011645 EXAMPLE 1 6-f(4-Chloro-phenvl)-hvdroxv-(3-methyl-3H-imidazol-4-vl)-methyl1-1-methyl-4-(3- trimethylsilanylethynyl-phenyl)-1H-ouinolin-2-one IA. 5-f2-(4-Chloro-phenvl)-f1,3ldioxolan-2-yn-3-(3-iodo-phenyl)-benzof’c|isoxazole2-{4-Chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (38.7 g, 127 mMol) was 5 suspended in 190 mL of methanol (MeOH) under an atmosphère of dry N2. To this solution ’was added (3-iodophenyl)acetonitrile (46.3 g, 190 mMol) and 25.4 g (625 mMol) of sodiumhydroxide (NaOH). The solution was then heated to reflux and reacted at this température for2 hours. The reaction mixture was cooled to ambient température and the MeOH wasremoved under vacuum. The resulting red oil was partitioned between dichloromethane 10 (DCM) and 0.1 N aqueous NaOH. The DCM layer was washed successively with 0.1 Naqueous NaOH and then brine. The DCM layer was dried over MgSO4l filtered andconcentrated under vacuum to give a dark red oil. The oil was stirred in MeOH and the titledcompound precipitated out as a yellow solid. The yellow solid was washed with MeOH anddried under vacuum to give 52.4 g of the titled compound which was used without further 15 purification. IB. r6-Amino-3-f4-chloro-benzoyl)-cvclohexa-2.4-dienvO-(3-iodo-phenyl)-methanone 5-[2-(4-Çhloro-phenyl)-[1,3]dioxolan-2-yl]-3-(3-iodo-phenyl)-benzo[c]isoxazoie (65.4 g, . 130 mMol) was dissolved in a solution of tetrahydrofuran (THF) (500 mL) and DCM (100 mL). 20 To this solution, was added 500 mL of titanium(lll) chloride (10 wt.% solution in 20-30 wt. %hydrochloric acid (HCl)) and the reaction mixture was stirred for 1 hour. An additional 100 mLof titanium(lll) chloride (10 wt.% solution in 20-30 wt. % HCl) was added to the reactionmixture and the reaction mixture was stirred for 2.5 hours. The reaction mixture was then 'poured into ice water and the resulting heterogeneous solution was extracted with DCM. The 2$ DCM layer was successively washed with aqueous saturated NaHCO3 and brine. The DCMlayer was dried over MgSO«, filtered and concentrated under vacuum to give titled compoundas an orange oil (60 g). The oil was used without further purification. IC. 6-(4-Chloro-benzovl)-4-(3-iodo-phenyl)-1H-quinolin-2-one[6-Amino-3-(4-chloro-benzoyl)-cyclohexa-2,4-dienyl]-(3-iodo-phenyl)-methan-one (60 30 g, 130 mMol) was dissolved in anhydrous toluene (450 mL) under an atmosphère of dry N2.

To this solution was added 180 mL of triethylamine (NEt3), 50 mL of acetic anhydride (Ac2O)and 1.60 g (13.0 mMol) of 4-dimethylaminopyridine (DMAP). The reaction mixture was thenheated to reflux and stirred at this température for 20 hours. The reaction mixture was cooledto ambient température and the precipitate was collected via suction filtration. The solid was 35 washed with ethyl ether (Et2O) and dried under vacuum to give of the titled compound (63 g)which was used without further purification. -25- 011645 ID. 6-(4-Chloro-ben2ovl)-4-(3-iodo-phenvl)-1-methyl-1H-quinolin-2-one 6-{4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1H-quinolin-2-one (63 g, 130 mMol) was dissoived in THF (500 mL) under an atmosphère of dry N2. To this solution, was added a 10N aqueous NaOH (550 mL), benzyltriéthylammonium chloride (13.S g, 60.5 mMol) and methyliodide (13.5 mL, 212.0 mMol). The reaction mixture was stirred at ambient température for 15hours after which time it was partitioned between DCM and water. The DCM layer was·successively washed with water (4 times) and then brine. The organic layer was dried overMgSO4, filtered and concentrated under vacuum to give 51.2 g of a yellow solid as the titledcompound which was used without further purification. IE. 6-(4-Chloro-benzovl)-1-methyM-{3-trimethylsilanvlethvnvl-phenvl)-1H-quinolin-2-one 6-(4-Chloro-benzoyl)-4-(3-iodo-phenyl)-1-methyl-1H-quinolin-2-one (9.98 g, 20.0mMol) was suspended in diethylamine (300 mL). To this solution was added 50 mL ofanhydrous Ν,Ν-dimethylformamide (DMF), (trimethylsilyl)acetylene (8.5 mL) andbis(tripheny!phosphine)-palladium(ll) chloride (1.40 g, 2.00 mMol). The flask was covered withaluminum foil and then copper(l) iodide (780 mg, 4.09 mMol) was added causing the reactionmixture to exotherm. After stirring overnight under an atmosphère of dry N2 at ambienttempérature, the reaction mixture was concentrated under vacuum and the residue waschromatographed on flash silica gel eluting with a gradient of DCM to MeOH/DCM (2:98) togive 8.55 g of the titled product as a solid. IF. 6-f (4-Chloro-phenvD-hvd roxy-f 2 -merca pto-3-methyl-3 H -imidazol-4-yl)-meth yll-1-methvl-4-(3-trimethvlsilanvlethynyl-phenvl)-1H-quinolin-2-one 2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissoived in anhydrous THF(200 mL) under an atmosphère of dry N2. The solution was cooled to -78°C and a solution ofterf-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was thenwarmed to 0°C. After'a yellow precipitate formed, the solution was cooled to -78°C and asolution of 6-(4-chloro-benzoyl)-1-methyl-4-(3-trimethylsiianyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mMol) in anhydrous THF (25 mL) was added. After 30 minutes, the solutionwas warmed to 0°C and stirred at this température for 1 hour. The reaction mixture was thenwarmed to ambient température and stirred overnight. The reaction was quenched with 20mL of saturated aqueous ammonium chloride (NH4CI) and then partitioned between DCM andwater. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentratedunder vacuum. The residue was chromatographed on flash silica gel eluting with a gradientfrom DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid. IG. 6-î(4-Chloro-phenvl)-hvdroxv-(3-methyl-3H-imidazol-4-vl)-methvn-1-methyM-(3-trimethvlsilanylethvnvl-phenyl)-lH-quinolin-2-one 6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1- methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (5.0 g, 8.6 mMol) was dissoived -26- 011645 in éthanol (40 mL) to whîch was added Raney™ nickel (ca. 10 g) and the reaction was heatedto reflux. More RANEY™ nickel was added every 20 minutes until mass spectral analysis ofthe reaction showed that the starting material had been consumed. The reaction mixture wascooled to ambient température and filtered through CELITE™ (diatomaceous earth). The 5 CELITE™ was washed with copious amounts of éthanol. The filtrâtes were combined andconcentrated under vacuum to give 3.88 g of the titled compound. C.l. m/z 552 [M+1]; 1H NMR (CD3OD) δ 7.64-7.75 (m, 3H), 7.17-7.48 (m, 9 H), 6.59(s, 1 H), 6.17 (s, 1 H), 3.79 (s, 3 H), 3.42 (s, 3 H), 0.23 (s, 9 H). EXAMPLE 2 |O 6-f(4-Chloro-phenyl)-hvdroxv-(3-methvl-3H-imidazol-4-yl)-methyll-4-(3-ethvnyl-phenvl)-1- methyl-1 H-quinolin-2-one

6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.88 g, 7.03 mMol) was dissolved in THF(10 mL) under an atmosphère of dry N2- To this solution was added a solution of 1.0 N 15 tetrabutylammonium fluoride in THF (20 mL, 20 mMol). The reaction mixture was stirredovernight at ambient température and was then concentrated under vacuum. The residuewas partitioned between 4-(dicyanomethylene)-2-methyl-6-(4-dimethylamino-styryl)-4H-pyran(DCM) and water. The DCM layer was saved and washed 3 more times with water and thenwith brine. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum. 20 The residue was chromatographed on. flash silica gel eluting with a gradient from DCM toMeOH/DCM (4:96) to give 3.01 g of the titled compound. C.l. m/z 480 [M+1]; 1H NMR (CD3OD) δ 7.75 (dd, J = 2.1, 8.9 Hz, 1H), 7.69 (s, 1 H), 7.66 (d. 8.5 Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 7.41 (t, J = 7.7 Hz. 1 H), 7.38 (s, 1 H), 7.29 (m,3 H), 7.23 (d, J = 1.7 Hz. 1 H), 7.17 (d, J = 8.5 Hz, 2 H), 6.59 (s, 1 H), 6.16 (s, 1 H), 3.79 (s, 3 25 H), 3.60 (s. 1 H), 3.42 (s, 3 H). Séparation of the Enantiomers of 6-l(4-Chloro-ph.envO-hvdroxv-(3-methvl-3H-imidazol-4-vl)- methyn-4-(3-ethynyl-phènvl)-1-methvl-1H-quinolin-2-one 6-[(4-Chioro-phenyl)-hydroxy-(3-methy!-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)- 1-methyl-1H-quinolin-2-one (4.96 g) was separated into its enantiomers and purified by high- 30 performance liquid chromatography over CHIRALPAK™ AD (manufactured by DaicelChemical Industries, LTD, Osaka, Japan) (20 μηη; eluent: Hexane/isopropanol/diethylamine85/15/ 0.1; 30°C). Under these conditions, 1.73 g of the faster eluting enantiomer A ({cx}q20 =-25.1 (c = 50.0 mg/5 mL)) was obtained and 2.07 g of the slower moving enantiomer B({α}ο^θ = +24.2 (c = 27.7 mg/5 mL)). Both enantiomers were >97% optically pure. 011645 -27- r EXAMPLE 3 6-fAmino-(4-chloro-phenvl)-(3-methvl-3H-imidazol-4-vl)-methvn-4-(3-ethvnyl-phenvl)-1-methvl- 1H-qüinolin-2-one 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methy!-1H-quinolin-2-one (1.75 mg, 3.65 mMol) was dissolved in 5.0 mL of thionyl chloride 5 (SOCI2) and stirred at room température under an atmosphère of dry N2 for 2 hours. The-reaction mixture was then concentrated under reduced pressure and the resulting solid wastaken up in toluene and concentrated under vacuum. The resulting solid was dissolved inTHF (15 mL) and to this mixture was added concentrated ammonium hydroxide (20 mL). Theréaction mixture was stirred at ambient température for 1 hour and was then partitionedt® between DCM and 1.0 N aqueous NaOH. The aqueous layer was extracted again with DCMand the organic layers were then combined, dried over Na2SO4, filtered and concentrated under vacuum to give a brown solid. The residue was chromatographed on flash silica geleluting with a gradient from MeOH/ethyl acétate (EtOAc)/ ammonium hydroxide (NH4OH)(5:95:0.1) to MeOH/EtOAc/N^OH (10:90:0.1) to give 643 mg of the titled compound. 15V C.l. m/z 479 [M+1]; 1H NMR (CD3OD) δ 7.84 (dd, J = 2.3, 9.1 Hz, 1H), 7.70 (d. 8.9

Hz. 1 H), 7.57 (s, 1 H), 7.51 (m, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.33 (s, 1 H), 7.28 (m, 2 H),7.21 (dd, J = 1.0, 7.7 Hz, 1 H), 7.10 (d, J = 8.5 Hz, 2 H), 6.96 (d. J = 1.3 Hz, 1 H), 6.57 (s. 1H), 6.10 (s, 1 H). 3.78 (s, 3 H), 3.60 (s, 1 H), 3.41 (s, 3 H). Séparation of the Enantiomers of 6-ÎAmino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-vl)- 2Û methvn-4-(3-ethvnvl-phenvD-1-methvl-1H-quinolin-2-one 6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethyny!-phenyl)- 1-methyl-1H-quinolin-2-one (5.25g) was separated into its enantiomers and purified by high-performance liquid chromatography over CHIRALCEL™ OD (manufactured by DaicelChemical Industries, LTD, Osaka, Japan) (20 gm; eluent: Hexane/isopropanol/diethylamine ^9 67/33/0.1; 25°C). Under these conditions, 2.29 g of the faster eluting enantiomer A was obtained and 1.60 g of the slower moving enantiomer B. Both enantiomers wére >97%optically pure. EXAMPLE 4 6-f(4-Chloro-phenvl)-hvdroxv-(3-methvl-3H-imidazol-4-vl)-methvH-1-methvM-f3-(3-methyl-but- 3P 1-ynyl)-phenyn-1H-quinolin-2-one

The same procedure was used as described in example 1 except that 3-methyl-1- butyne was used in the place of (trimethylsilyl)acetylene in step 1E to give the titledcompound. C.l. m/z 522 [M+1]; 1H NMR (CDCI3) δ 7.60 (m, 2 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.37 (d,J = 7.9 Hz, 1 H), 7.25-7.29 (m, 5 H), 7.17 (d, J = 8.7 Hz, 2 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.60 -28- ίο 15 20 25 30 011645 (s, 1 H), 6.31 (brs, 1 H), 3.70 (s. 3 H), 3.43 (s. 3 H), 2.79 (m. J = 6.9 Hz, 1 H), 1.26 (d, J = 6.9Hz, 6 H). EXAMPLE 5 6-f(4-Chloro-phenyl)-hydroxv-(3-methvl-3H-imidazol-4-vO-methvn-4-i3-(3,3-dimethvl-but-1- vnyl)-phenyl1-1-methvl-1 H-quinolin-2-one

The same procedure was used as described in example 1 except that 3,3-dimethyl-1- 'butyne was used in the place of (trimethylsilyl)acetylene in step 1E to give the titledcompound. C.l. m/z 536 [M+1]; 1H NMR (CDCI3) δ 7.84 (brs, 1 H), 7.60 (m, 1 H), 7.40 (m. 3 H).7.21-7.27 (m, 4 H), 7.15 (d, J = 8.5Hz, 2 H), 7.02 (d, J = 7.3 Hz, 1 H), 6.61 (s, 1 H), 6.34 (brs, 1 H), 3.70 (s, 3 H), 3.48 (s, 3 H), 1.30 (s, 9 H). EXAMPLE 6 6-f(4-Chloro-phenvl)-hvdroxv-(3-methvl-3H-imidazol-4-yl)-methvl1-1-methvl-4-[3-(4-methvl- pent-1-ynyl)-phenvn-1H-quinolin-2-one

The same procedure was used as described in example 1 except that 4-methyl-1-pentyne was used in the place of (trimethylsilyl)acetylene in step 1E to give the titledcompound. C.l. m/z 536 [M+1]; ’H NMR (CDCI3) δ 7.84 (brs, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 7.39-7.44 (m, 2 H), 7.25-7.30 (m, 5 H), 7.17 (d, J = 8.3 Hz, 2 H), 7.05 (d, J = 7.2 Hz, 1 H), 6.63 (s. 1H), 6.36 (brs, 1 H), 3.72 (s, 3 H), 3.49 (s, 3 H), 2.31 (d, J = 6.4 Hz, 2 H), 1.91 (m. 1 H), 1.03 (d, J = 6.6 Hz, 6 H). EXAMPLE 7 6-f(4-Chloro-phenvl)-(3-methvl-3H-imidazol-4-vl)-i1.2.4|triazol-1-vl-methvn-4-(3-(3,3-dimethvl- but-1 -ynyO-phenyll-l -methvl-1 H-quinolin-2-one 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1 -ynyl)-phenyl]-1-methyl-1H-quinolin-2-one (330 mg, 0.633 mMol) was dissolved in 4 mLof thionyl chloride and stirred at ambient température under a stream of dry N2 for 2 hours.

The reaction mixture was then concentrated under vacuum and toluene (5 mL) was added tothe reaction mixture which was subsequently concentrated under vacuum to give a yellowsolid. 210 mg of the yellow solid was dissolved in 5.0 mL of anhydrous DMF under anatmosphère of dry N2. To this solution was added 800 mg of potassium carbonate and 300 mg of 1,2,4-triazole and the reaction mixture was subsequently heated to 80°C and stirredovernight at this température. The reaction mixture was then concentrated under vacuum andpartitioned between EtOAc and water. The EtOAc layer was washed 3 more times with waterand then with brine. The EtOAc layer was then dried over Na2SO4, filtered and concentratedunder vacuum to give a yellow solid. The solid was chromatographed on flash silica gel 35 -29- 011645 eluting with a gradient of MeOH/DCM/NH4OH (2/98/0.1) to MeOH/DCM/NH4OH (7/93/0.1) togive 150 mg of the titled product as a white solid. 1H NMR (CDCI3) δ 8.06 (s, 1 H), 7.89 (s, 1 H), 7.59 (brs, 1 H), 7.41 (d, J = 8.7 Hz, 2 H), 1 H), 7.22-7.27 (m, 5 H), 7.00-7.05 (m. 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 6.67 (s, 1 H), 6.54(brs, 1 H), 3.75 (s, 3 H), 3.08 (s, 3 H), 1.31 (s, 9 H). EXAMPLE 8 6-f(4-Chloro-phenvl)-(3-methyl-3H-imidazol-4-vl)-f1,2.4)triazol-1-vl-methvn-1-methvl-4-(3-(3- methvl-but-1-vnvl)-phenyl1-1H-quinolin-2-one

The same procedure was used as described in example 7 except that 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1 -methyl-4-[3-(3-methyl-but-1 -ynyl)-phenyl]-1H-quinolin-2-one was used in the place of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1 H-quinolin-2-one to give the titled compound. ’H NMR (CDCI3) δ 8.06 (s, 1 H). 7.90 (s, 1 H), 7.43-7.48 (m, 2 H),7.20-7.34 (m, 6 H),7.01 (d. J = 8.1 Hz, 1 H). 6.98 (s, 1 H), 6.79 (m, 3 H), 6.70 (s, 1 H), 3.77 (s, 3 H), 3.28 (s. 3 H).2.80 (m, 1 H), 1.26 (d, J = 6.9 Hz. 6 H). EXAMPLE 9 6-f(4-Chloro-phenvl)-hvdroxv-(3-methyl-3H-imidazol-4-yl)-methvn-4-(3-ethynyl-4-fluoro- phenyQ-1 -methyl-1 H-quinolin-2-one 9A. 4-Bromomethvl-1-fluoro-2-iodo-benzene 4-Fluoro-3-iodotoluene (50 g, 210 mMol), N-bromosuccinimide (37.7 g, 212 mMol)and 2,2'-azobis-(2-methylpropionitrile) (348 mg, 2.12 mMol) were dissoived in carbontetrachloride (300 mL) under an atmosphère of dry N2. The mixture was heated to reflux for 4hours and then cooled to ambient température. The mixture was concentrated under vacuumand triturated with Et2O. The filtrate was successively washed with water, aqueous saturatedNaHCO3 and brine. The ether layer was dried over MgSO4, filtered and concentrated undervacuum to give a red oil. The oil was chromatographed on flash silica gel eluting withhexanes to give 33.8 g of the titled compound as a white solid. -30- 011645 9Θ. (4-Fluoro-3-iodo-phenyl)-acetonitrile 4-Bromomethyl-1-fluoro-2-iodo-benzene (33.8 g, 107 mMol) was added to 240 ml ofa 0.5 M solution of lithium cyanide in DMF. The reaction mixture was heated to 80°C under anatmosphère of dry N2 and stirred overnight at this température. The mixture was then cooled 5 to ambient température and partitioned between Et2O and 0.1 N aqueous NaOH. The Et2Olayer was then washed 4 more times with 0.1 N aqueous NaOH. The Et2O layer was thendried over MgSO4l filtered and concentrated under vacuum to give 24.7 g of the titledcompound as a red solid which was used without purification. 9C. 6-î(4-Chloro-phenyl)-hvdroxv-(3-methvl-3H-imidazol-4-yl)-methyll-4-(3-ethynvl-4-fluoro-phenyl)-1-methyl-1H-quinolin-2-one

The procedure was used as that of examples 1 and 2 except that (4-fluoro-3-iodophenyl)acetonitrile was used in the place of (3-iodophenyl)acetonitrilé in step 1A to givethe titled compound. C.l. m/z 498 [M+1]; 1H NMR (CDCI3) δ 7.61 (d, J = 8.1 Hz, 1H), 7.53 (brs, 1 H), 7.3615 (d, 9.0 Hz, 1 H), 7.04-7.33 (m, 8 H), 6.52 (s, 1 H), 6.21 (brs, 1 H), 3.67 (s, 3 H), 3.38 (s, 3 H), . ! 3.36 (s, 1 H). EXAMPLE 10 6-f(4-Chloro-pheny0-hvdroxv-(3-methyl-3H-imidazoU4-vr>-methvÎ1-1-methvl-4-(3-phenylethvnvl- phenvl)-1 H-quinolin-2-one

The procedure was used as that of example 1 except that phenylacetylene was usedin the place (trimethylsilyl)acetylene in step 1E to give the titled compound. C.l. m/z 556 [M+1]; 1H NMR (CDCI3) δ 7.60 (dd, J = 2.1, 8.8 Hz, 1H), 7.50 (m, 3 H), 7.43 (brs, 1 H), 7.21-7.37 (m, 9 H), 7.17 (d, J = 8.5 Hz, 2 H), 7.08 (d. J = 7.5 Hz, 1 H). 6.61 (s,1 H), 6.26 (brs, 1 H), 3.69 (s, 3 H), 3.38 (s, 3 H). 25 EXAMPLE 11 6-H4-Chloro-phenvl)-hvdroxv-(3-methvl-3H-tmida2Ol-4-vr)-methyn-4-f3-(4-hvdroxv-but-1-ynv0- phenvfl-1-methyl-1H-quinolin-2-one 11 A. 6-(4-Chloro-benzoyl)-1-methvl-4-f3-(4-trityloxv-but-1-vnyl)-phenyn-1H-quinolin- 2-one 6-{4-Chloro-benzoyl)-4-[3-(4-hydroxy-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one[1.41 g, 3.20 mMol), which was prepared by substituting 3-butyn-1-ol for(trimethylsilyl)acetylene in step 1E of example 1, and triethylamine (900 mL, 6.40 mMol) weredissolved in DCM (15 mL) under an atmosphère of dry N2. To this solution was addedtriphenylmethyl chloride (980 mg, 3.50 mMol) and the mixture was stirred at ambient 35 température for 4 hours. The reaction mixture was then partitioned between Et2O/EtOAc andwater. The organic layer was washed again with water and then with saturated aqueous -31- 10 15 20 25 30 35

NaHC03, dried over MgS04, filtered and concentrated under vacuum to give a white foam asthe titled compound which was used without further purification. 11B. 6-f(4-Chloro-phenyl)-hydroxv-(3-methyl-3H-imidazol~4-vl)-methyli-4-[3-(4-hvdroxv-but-1-vnvl)-phenvP-1-methyl-1H-quinolin-2-one 2-Mercapto-1-methylimidazole (400 mg, 3.50 mMol) was dissolved in anhydrous THF(7.0 mL) under a stream of dry N2. The solution was then cooled to -78°C and a solution of 2.8 mL of a 2.5 M solution of n-butyllithium in hexanes was then added. After the addition wascomplété, the reaction mixture was warmed to ambient température and stirred at thistempérature for 1 hour. The reaction mixture was then cooled to -78°C and a solution of (4-chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-one in THF (7.0mL) was added to the mixture. The reaction was warmed to ambient température and stirredovernight. The reaction mixture was quenched with saturated aqueous NH4CI (25 mL) andpartitioned between DCM and water. The DCM layer was dried over Na2SO4, filtered andconcentrated under vacuum to give a green solid. The green solid was dissolved in 30 mL ofacetic acid (AcOH) and the solution was cooled to about 5°C. To this solution was added 2.0mL of 30% aqueous hydrogen peroxide (H2O2) dropwise. After the addition was complété, thereaction mixture was stirred at ambient température for 30 minutes. The reaction mixture wasthen cooled to 0°C, 200 mL of water was added and the reaction was basified to pH=10 withthe slow addition of NaOH. Sodium sulfite was added portionwise until testing with starch-iodine paper showed no H2O2 left. The reaction mixture was partitioned between DCM andwater. The DCM layer was dried over Na2SO4, filtered and concentrated under vacuum togive a green solid. The green solid was dissolved in a solution of MeOH/DCM (25:3) to whichwas added 3 N aqueous HCl (3.0 mL). The solution was then heated to 68°C and reacted atthis température for 2 hours. The solution was concentrated under vacuum to a thick sludgeand then was partitioned between DCM and 0.01 N aqueous NaOH. The DCM layer wasconcentrated under vacuum and chromatographed on flash silica gel eluting with a gradient ofMeOH/EtOAc/NH„OH (5:95:.01) to MeOH/EtOAc/NH4OH (10:90:.01) to give the titledcompound. C.l. m/z 524 [M+1]; ’H NMR (CDCI3) δ 7.53 (m, 1 H), 7.43 (brs. 1 H), 7.34 (d, J = 7.9Hz, 1 H), 7.16-7.26 (m, 8 H). 7.03 (d, J = 7.5 Hz, 1 H), 6.38 (s, 1 H), 6.28 (s, 1 H), 3.73 (m, 2H), 3.52 (s, 3 H), 2.39 (s, 3 H), 2.61 (m, 2 H). EXAMPLE 12 6-i(4-Chloro-phenyl)-hvdroxv-f3-methyl-3H-imidazol-4-vl)-methyl]-1-cyclopropvlmethvl-4-f3- ethynvl-phenvl)-1H-quinolin-2-one 12A. 6-(4-Chloro-benzovl)-1-cyclopropylmethvl-4-f3-iodo-phenvl)-1H-quinolin-2-one

A solution of 6-(4-Chloro-benzoyI)~4-(3-iodo-phenyl)-1H-quinolin-2-one (9.68 g, 19.9mmol), prepared as described in PCT international patent application publication number WO -32- 011645 97/21701 (published June 19, 1997) (3.10 g, 7.87 mmol) in DMF (70 mL) was treated withcésium carbonate (23.1 g, 19.9 mmol) and (bromomethyl)cyclopropane (5.37 g, 39.8 mmol).The reaction mixture was stirred at room température for 12 hours, diluted withdichloromethane (75 mL), and washed with 1N HCl (2 x 50 mL) and brine (100 mL). Thecombined organic extracts were dried (MgSC^), filtered, and concentrated in vacuo to give ablack residue. Purification by flash column chromatography (silica, ethyl acetate:petroleumether 1:9 - 3:7) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one (6.79 g, 63%) as a yellow solid. C.l. m/z 540 [M+1]; 1H NMR (CDCI3): δ = 8.05 (dd, J = 9.0, 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H). 7.80-7.77 (m. 2H), 7.71-7.64 (m, 3H), 7.50-7.46 (m, 2H), 7.37 (dd, J = 7.8, 1.2Hz, 1H). 7.22-7.17 (m, 1H), 6.68 (s, 1H), 4.32 (d, J = 6.8 Hz, 2H), 1.34-1.23 (m, 1H), 0.64-0.56(m, 4H). 12B. 6-(4-Chloro-benzovl)-1-cvclopropylmethvi-4-(3-trimethvlsilanvlethynvl-phenyl)-1H-quinolin-2-one A solution of 6-(4-chloro-benzoyI)-1-cyclopropylmethyl-4-(3-iodo-phenyl)-1H-quinolin-2-one (4.0 g, 7.41 mmol) in DMF/diethylamine (1:1, 80 mL) was treated with palladium (II)bis(triphenyl)phosphine chioride (0.26 g, 0.37 mmol), trimethylsilylacetylene (1.09 g, 11.1mmol), and copper (I) iodide (0.21 g, 1.09 mmol). The reaction mixture was stirred at roomtempérature for 3 hours, concentrated in vacuo, poured into H2O (450 mL), and filtered to givea crude brown foam. Purification by flash column chromatography (silica, ether:Petroleumether 1:1) gave 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 92%) as a yellow solid. C.l. m/z 510 [M+1]; 1H NMR (CDCI3): δ = 8.08 (dd, J = 8.9, 1.9 Hz, 1 H), 7.92 (d, J = 1.7 Hz, 1H), 7.72-7.65 (m, 3H), 7.58-7.29 (m, 6H), 6.69 (s, 1H), 4.33 (d, J = 7.1 Hz, 2H), 1.34-1.25 (m, 1H), 0.63-0.55 (m, 4H), 0.26 (s, 9H). 12C. 6-f(4-Chloro-phenvl)-hydroxv-(3-methvl-3H-imidazol-4-yl)-methvn-1- cvclopropylmethvl-4-(3-ethvnvl-phenyl)-1H-quinolin-2-one A solution of 2-(tert-butyl-dimethyl-silanyl)-1-methyl-1H-imidazole (1.71 g, 8.7 mmol) inTHF (40 mL) at -78°C was treated with sec-butyllithium (1.3 M in cyclohexane, 8.4 mL, 10.9mmol). The réaction mixture was warmed to 0°C, stirred for 3 hours, and cooled to -78°C. Asolution of 6-(4-Chloro-benzoyI)-1-cyclopropylmethyl-4-(3-trimethylsiIanylethynyl-phenyl)-1H-quinolin-2-one (3.47 g, 6.8 mmol) (2.87 g, 6.4 mmol) in THF (20 mL) was cannulated into thereaction mixture, slowly warmed to room température, and stirred overnight. The reactionmixture was quenched with ammonium chioride (12 mL), diluted with ether (200 mL), andwashed with H2O (200 mL) and brine (200 mL). The organic layer was dried (Na2SO4),filtered, and concentrated in vacuo to give 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H- -33- 011645 imidazol-4-yI]-(4-chloro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl-4-(3- trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (4.50 g) as a yellow foam. The crudematerial was used in the next step without any further purification. A solution of 6-[[2-(tert-Butyl-dimethyl-silanyl)-3-methyl-3H-imidazol-4-yl]-(4-chioro-phenyl)-hydroxy-methyl]-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one (4.50 g crude) in THF (100 mL) was treated with tetrabutylammonium chloride (1 M inTHF, 10.0 mmol). The reaction mixture was stirred at room température for 12 hours, pouredintô H2O (200 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organicextracts were washed with 1N HCl (100 mL), aqueous NaHCO3 (1θθ mL), and brine (100mL), dried (MgSO4), filtered, and concentrated in vacuo to give a light green foam.Purification by flash column chromatography (silica, EtOAc:pet. etherN^OH 1:1:0.01) gave6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethy!-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.82 g, 51%) as a yellow powder. C.l. m/z 520 [M+1]; 1H NMR (CDCI3): δ = 7.59 (dd, J = 9.1, 2.1 Hz. 1H), 7.53-7.51 (m,2H), 7.35-7.25 (m, 6H), 7.18-7.15 (m, 3H), 6.60 (s, 1H), 6.30 (s, 1H), 4.25 (d, J = 7.1 Hz, 2H),3.37 (s, 3H). 3.13 (s, 1H), 1.76 (br.s, 1 H), 1.39-1.25 (m, 1H), 0.59-0.51 (m, 4H). Séparation of the Enantiomers of 6-f(4-Chloro-phenyl)-hydroxv-(3-methyl-3H-imidazol- 4-vl)-methvr)-1-cvclopropylmethvl-4-(3-ethynvl-phenyl)-1H-Quinolin-2-one 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.02 g) was separated into its enantiomers andpurified by high-performance liquid chromatography over CHIRALCEL™ OD (manufactured byDaicel Chemical Industries, LTD, Osaka, Japan) (20 pm; eluent:hexane/isopropanol/diethylamine 65/35/0.1; 25°C). Under these conditions. 0.42 g of thefaster eluting enantiomer A was obtained and 0.43 g of the slower eluting enantiomer B. Bothenantiomers were >97% optically pure. EXAMPLE 13 6-ÎAmino-(4-chloro-phenvl)-(3-methvl-3H-imidazol-4-vl)-methyfl-1-cvclopropvlmethvl-4-(3- ethynyl-phenyl)-1H-quinolin-2-one

The same procedure that was used in example 3 was followed except 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (1.80 g, 3.5 mmol) was used in place of 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl) -1-methyl-1H-quinolin-2-one to give 6-[Amino-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-4-{3-ethynyl-phenyl)-1H-quinolîn-2-one (1.12 g, 62%) as a yellow foam. C.l. m/z 519 [M+1]; 1H NMR (CDCI3): δ = 7.57-7.51 (m, 3H), 7.43 (s, 1H). 7.36-7.31 (m, 2H), 7.26-7.22 (m, 2H), 7.18 (d, J =7.7 Hz, 1 H), 7.09-7.05 (m, 3H), 6.63 (s, 1H), 6.32 (s, -34- Ό11645 1Η). 4.28 (d, J= 7.1 Hz, 2H), 3.39 (s, 3H), 3.13 (s, 1H). 2.11 (br.s, 2H), 1.31-1.27 (m. 1H).0.61-0.52 (m, 4H). EXAMPLE 14 6-f(4-Chloro-phenyl)-(3-methvl-3H-imidazol-4-yl)-fl,2,4)triazol-1-yl-methvn-1-5 cyclopropvlmethvl-4-(3-ethynyl-phenylMH-quinolin-2-one

The same procédure that was used in example 7 was fcllowed except 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidszol-4-yl)-methyl]-1-cyciopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-cne was used in place cf 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one to give 6-[(4-Chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,4]triazol-1-yl-methyl]-1-cyclopropylmethyl-4-(3-ethynyl-phenyl)-1H-quinolin-2-one (21.0 mg, 55%) as a yellow film. C.l. m/z 571 [M+1]; ’H NMR (CDCI3): δ = 8.06 (s, 1H), 7.89 (s, 1 H). 7.56-7.52 (m,3H), 7.34-7.25 (m. 5H), 7.14 (dd. J= 7.8, 1.4 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.95-6.91 (m,2H), 6.66 (s, 1H), 6.55 (s, 1H), 4.26 (d. J = 6.9 Hz, 2H), 3.14 (s, 1H), 3.06 (s, 3H). 1.30-1.23 15 (m, 1H), 0.61-0.52 (m, 4H); IR: vmax = 3500, 1650, 1500, 1325, 1275, 1125, 1100, 1025 cm·’.

Claims

35- 011645 CLAIMS What is claimed is:

1. A compound of the formula 1

or a pharmaceutically acceptable sait, prodrug or solvaté thereof wherein: the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2-one 5 ring is a single or double bond; R1 is selected from H, CrC,Q alkyl, -(CR13R14),C(O)R12, -{CR^R^qCiOJOR15,^CR”R14),ORn, -(CR13R14),SO2R15, -(CR13R14)t(C3-Cl0 cycloalkyl). -(CR13R14),(C6-C10 aryl),and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is aninteger from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a 10 Ο6-Ο10 aryl group, a Cs-CB saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R1 groups, except H but including any optional fused rings referred to above, areoptionally substituted by 1 to 4 R® groups; R2 is halo, cyano, -C(O)OR15, or a group selected from the substituents provided inthe définition of R12; 15 each R3, R4, Rs, R6, and R7 is independently selected from H, C^Cw alkyl, C2-C10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR12, -C(O)R12,-C(O)OR12, -NR13C(O)OR15, -OC(O)R12, -NR13SO2R15, -SO2NR12R13, -NR13C(O)R12, -C(O)NR12R13, -NR12R13, -CH=NOR12, -S(O)jR12 wherein j is an integer from 0 to 2,-(CR13R14X(C6-Cw aryl), -(CR13R14),(4-10 membered heterocyclic), -(CR’3R14),(C3-C10 20 cycloalkyl), and -(CR13R14)tCsCR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groups t is an integer from 0 to 5; the cycloalkyl, aryl and heterocyclic moieties of the foregoing groupsare optionally fused to a C6-C10 aryl group, a C5-CB saturated cyclic group, or a 4-10membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groupsare optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, 25 trifluoromethyl, trifluoromethoxy, azido, -NR13SO2R15, -SO2NR12R13, -C(O)R12, -C(O)OR12, -OC(O)R12, -NR13C(O)OR15, -NR13C(O)R12, -C(O)NR12R13, -NR12R13, -OR12, C,-C,o alkyl, C2- -36- 011645 Cio alkenyl, C2-C10 alkynyl, -(CR R )t(C£-Cio aryl), and -(CR 3R1 ))(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5; R8 is H, -OR12, -NR12R13, -NR12C(O)R13, cyano, -C(O)OR13, -SR12, -(CR13R14),(4-10membered heterocyclic), wherein t is an integer from 0 to 5, or C,-C6 alkyl, wherein said 5 heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents; R9 is -(CR13R14),(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R6 substituents; each R10 and R11 is independently selected from the substituents provided in the définition of R6; ^0 each R12 is independently selected from H, C,-C10 alkyl, -(CR13R14)t(C3-Ci0 cycloalkyl), -(CR13R14),(C6-C10 aryl), and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integerfrom 0 to 5; said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C,0aryl group, a Cs-C8 saturated cyclic group, or a 4-10 membered heterocyclic group; and theforegoing R12 substituents, except H, are optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido,-C(O)R13, -C(O)OR13, -OC(O)R13, -NR13C(O)R14, -C(O)NR13R14, -NR13R14, hydroxy, C,-C6alkyl, and C,-C6 alkoxy; each R13 and R14 is independently H or C)-C6 alkyl, and where R13 and R14 are as-(CR13R14)q or (CR13R14), each is independently defined for each itération of q or t in excess of 20 t ,, R15 is selected from the substituents provided in the définition of R12 except R15 is not H; R16 is selected from the list of substituents provided in the définition of R12 and-SiR17R18R19; 25 R17, R18 and R19 are each independently selected from the substituents provided in the définition of R12 except R17, R18 and R19 are not H; and provided that at least one of R3, R4 and Rs is -(CR13R14),C=CR16 wherein t is aninteger from 0 to 5 and R13, R14, and R16 are as defined above.
2. A compound according to claim 1 wherein R1 is H, CrC6 alkyl, or 30 cyclopropylmethyl; R2 is H; R3 is -C=CR16; and R8 is -NR12R13, -OR12, or a heterocyclic group selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl, wherein said heterocyclic group isoptionally substituted by an R6 group.
3. A compound according to claim 2 wherein R9 is imidazolyl optionally substituted byCi-C6 alkyl; R8 is hydroxy, amino, or triazolyl; and R4, R5, R10 and R11 are each independently 35 selected from H and halo.
4. A compound according to claim 1 wherein R1 is -(CR13R14)t(C3-Cl0 cycloalkyl)wherein t is an integer from 0 to 3; R2 is H; and R8 is -NR12R13, -OR12, or a heterocyclic group -37- 011645 seiected from triazolyl, imidazolyl. pyrazolyl, and piperidinyl, wherein said heterocyciic group isoptionally substituted by an R6 group.
5. A compound according to claim 4 wherein R9 is imidazolyl optionally substituted byCrC6 alkyl; R8 is hydroxy, amino, or triazolyl; R3 is -C=CR16; R4, R5, R10 and R1’ are each 5 independently seiected from H and halo; and R1 is cyclopropylmethyl.
6. A compound according to claim 5 wherein R3 is ethynyl.
7. A compound according to claim 2 wherein R3 is ethynyl.
8. A compound according to claim 1 wherein said compound is seiected from the groupconsisting of: 6-[(4-Chloro-phenyI)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1H-quinolin-2-one (enantiomer A); 6-[(4-Ch!oro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one (enantiomer B); 6-[Amino-(4-chloro-phenyl)-(3-methy!-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1-methyl-1 H-quinolin-2-one (enantiomer A); 6-[Amino-(4-chiOro-phenyI)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-1 -methyl-1 H-quinolin-2-one (enantiomer B); 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-4-fluoro-phenyl)-1-methyl-1 H-quinolin-2-one; 2Q and the pharmaceutically acceptable salts, prodrugs and solvatés of the foregoing compounds.
9. Use of a compound of claim 1 for the manufacture of a médicament for thetreatment of abnormal cell growth.
10. The use according to claim 9, wherein said abnormal cell growth is cancer.
11. The use according to claim 10 wherein said cancer comprises lung cancer,bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the analrégion, stomach cancer, colon cancer, hreast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervïx, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer ofthe adreaal gland, sarcoma of soft tissue, cancer of the urethra,cancer of the pénis, prostate cancer, chronic or acute leukemia, lymphocytic iymphomas,cancer of the bladdcr, cancer of the kioncy or ureter, rénal cell carcinoma, carcinoma of dierénal pelvis, neoplasms ofthe central nervous System (CNS), primarv CNS iymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of two or moreof the foregoing cancers. -38- 011645
12, The use according to claim 9, wherein said abnormal cell growth is a bcnignproliférative disease.
13. The use according to claim 12, wherein said benign proliférative diseasecomprises psoriasis, benign prostatic hypertrophy, or restinosis.
14. Use of a compound of daim 1 in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics. growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiera, anti-hormones, and anti-androgensfor the manufacture of a médicament for the treatment of abnormal cell growth. ,0 15- A pharmaceutical composition for the treatment of abnormal cell growth in a mammal which comprises an amount of a compound according to claim 1 that is effective ininhibiting famesyl protein transferase and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition according to claim 1J) wherein said abnormal cellgrowth is cancer. 15 A pharmaceutical composition according to claim 16 wherein said cancer comprises lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of theanal région, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the 20 vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of thepénis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of thebladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis, 25 neoplasms of the central nervous System (CNS), primary CNS lymphoma, spinal axis tumors,brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers. 18 A pharmaceutical composition according to claim 1S wherein said abnormal cellgrowth is a benign proliférative disease. 1e?. A pharmaceutical composition according to claim 18 wherein said benign 30 proliférative disease comprises psoriasis, benign prostatic hypertrophy, or restinosis. A pharmaceutical composition for the treatment of abnormal cell growth in a mammal which comprises an amount of a compound according to claim 1 that is effective intreating abnormal cell growth and a pharmaceutically acceptable carrier. -39- 011645 Zl A pharmaceutical composition for the treatment of abnormal cell growth in amammal which comprises a therapeutically effective amount of a compound of claim 1 incombination with a pharmaceuticaliy acceptable carrier and an anti-tumor agent selected fromthe group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biological response modifiers, anti-hormones, and anti-androgens. 2Z. Use of a compound of claim 1 for the manufacture of a médicament for thetreatment of an infection. 23·· The use according to claim 2JL, wherein said infection is hepatitus deltavirus or malaria, A pharmaceutical composition for the treatment of an infection in a mammal,wherein said infection is facilitated by farnesyl protein transferase, which comprises atherapeutically effective amount of a compound of claim 1 and a pharmaceuticaliy acceptablecarrier. 25? The pharmaceutical composition of claim 24-wherein said infection is hepatitus deltavirus or malaria.
26. A compound of formula 28

wherein R1 is selected from H, C,-C10 alkyl, -(CR13R14)qC(O)R12, -(CR,3R14)qC(O)OR15,-(CR13R14)<jOR12, -{CR’3R14)qSO2R15, -(CR13R14),(C3-C,0 cycloalkyl), -(CR,3R14),(C6-C,0 aryl),and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is aninteger from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to aC6-C10 aryl group, a C5-CB saturated cyclic group, or a 4-10 membered heterocyclic group; andthe foregoing R1 groups, except H but including any optional fused rings referred to above, areoptionaliy substituted by 1 to 4 R6 groups; R2 is halo, cyano, -C(O)OR15, or a group selected from the substituents provided in the définition of R12; -40- 011645 each R3, R4, R5, R6, and R7 is independently selected from H, Ci-Cw alkyl. C2-C10alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR12, -C(O)R12,-C(O)OR12, -NR13C(O)OR15, -OC(O)R12, -NR13SO2R1s, -SO2NR12R13, -NR13C(O)R12, -C(O)NR12R13, -NR12R13, -CH=NOR12, -S(O)jR12 wherein j is an integer from 0 to 2,-(CR13R14),(C6-C10 aryl), -(CR13R14),(4-10 membered heterocyclic), -(CR13R14),(C3-C,Ocycloalkyl), and -(CR13R14),C=CR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groups't is an integer from 0 to 5; the cycloalkyl, aryl and heterocyclic moieties of the foregoing groupsare optionally fused to a C6-Cw aryl group, a C5-Ce saturated cyclic group, or a 4-10membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groupsare optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, azido, -NR13SO2R1S, -SO2NR12R13, -C(O)R12, -C(O)OR’2,-OC(O)R12, -NR13C(O)OR1S, -NR13C(O)R12, -C(O)NR12R13, -NR12R13, -OR12, C,-C10 alkyl, C2-C,o alkenyl, C2-C10 alkynyl, -(CR13R14)t(C6-Ci0 aryl), and -(CR13R14)t(4-10 memberedheterocyclic), wherein t is an integer from 0 to 5; each R10 and R11 is independently selected from the substituents provided in thedéfinition of R6; each R12 is independently selected from H, Ο,-Ο,ο alkyl, -(CR13R14),(C3-C10 cycloalkyl),-(CR13R14)t(C6-Cl0 aryl), and -(CR13R14)t(4-10 membered heterocyclic), wherein t is an integerfrom 0 to 5; said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10aryl group, a Cs-Cg saturated cyclic group, or a 4-10 membered heterocyclic group; and theforegoing R12 substituents, except H, are optionally substituted by 1 to 3 substituentsindependently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido,-C(O)R13, -C(O)OR13, -OC(O)R13, -NR13C(O)R14, -C(O)NR13R14, -NR13R14, hydroxy, CrC6alkyl, and CrC6 alkoxy; each R13 and R14 is independently H or Ci-C6 alkyl, and where R13 and R14 are as-(CR13R14), or (CR13R14)t each is independently defined for each itération of q or t in excess of1; R15 is selected from the substituents provided in the définition of R12 except R15 is notH; R16 is selected from the list of substituents provided in the définition of R12 and-SiR17R18R19; R17, R18 and R19 are each independently selected from the substituents provided inthe définition of R12 except R17, R18 and R19 are not H; and provided that at least one of R3, R4 and R5 is -(CR13R14),C=CR16 wherein t is aninteger from 0 to 5 and R13, R14, and R18 are as defined above. 2?. A compound selected from the group consisting of -41- 011645 6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1 H-quinolin-2-one; 6-[(4-Chloro-phenyl)-hydroxy-(2-mercapto-3-methyl-3H-imidazol-4-yl)-methyl]-1- methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one; 5 6-{4-Chloro-benzoyl)-1-methyl-4-(3-trimethylsilanylethynyl-phenyl)-1H-quinolin-2-one; 6-(4-Chloro-benzoyl)-1-methyl-4-[3-(4-trityloxy-but-1-ynyl)-phenyl]-1H-quinolin-2-one; and, 6-(4-Chloro-benzoyl)-1-cyclopropylmethyl-4-(3-trimethylsilanylethynyl-phenyl)-1H- quinolin-2-one. ® Ί&. A method of preparing a compound of claim 1 wherein R3 is ethynyl, which comprises treating a compound of formula 29

tetrabutyiammonium fluoride.